Atherosclerosis and ischemic heart disease remain the major cause of death of Americans. Elevated serum cholesterol levels present a major risk factor for atherosclerosis and related complications including myocardial infarction, heart failure, and cerebral stroke. Intervention studies performed in middle-aged men demonstrated a marked reduction in the incidence of cardiovascular events after the lowering of elevated total and low-density lipoprotein cholesterol (LDL-C) levels. The Cholesterol and Recurrent Events (CARE) trial and the Scandinavian Simvastatin Survival Study (4S)(1994, Lancet 344:1383-1389) have further shown that both women and elderly patients with prior history of ischemic heart disease benefit from cholesterol lowering therapy. (Miettinen et al., 1988, Arch. Intern. Med. 148:36-69; Sacks et al., 1996, New Eng. J. Med. 335:1001-1009).
The most effective cholesterol lowering drugs are statins, which lower cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme which catalyzes the limiting step in cholesterol biosynthesis (Goldstein et.al., 1984, J. Lipid Res. 25, 1450-1461). Compared to treatment regimens with other lipid lowering agents, such as the bile acid sequestrants (colestipol and cholestyramine), nicotinic acid, fibric acid (gemfibrozil and clofibrate), probucol, and experimental ACAT inhibitors, statin therapy has been found to bear several favorable features. Statins achieve extensive lowering of LDL-C, leading to an overall reduction in mortality, and are cost effective. Due to substantial reduction of hospital admissions and rates of coronary intervention. Statins also achieve better compliance than other treatments, as a result of their once-daily administration and few side effects. Combination of statins with other agents is considered necessary for patients with severe, complex or refractory lipid disorders. Furthermore, large clinical trials have suggested regression of atherosclerotic lesions by aggressive lipid lowering therapy (Schell and Myers, 1997, Prog. on Cardiovascular Diseases 39:483-496). To complement the statins and achieve successful reduction of cholesterol in statin-resistant subjects, identification of new lipid lowering agents with a different mechanism of action than statins remains a major focal point in contemporary atherosclerosis research. Since the HMG CoA inhibitors are ineffective in the mouse, this animal provides a useful model for screening novel agents capable of lowering cholesterol levels by a different mechanism of action than statins.
There is a need for new lipid lowering agents that are effective to lower total cholesterol and/or LDL-C, for the treatment of high cholesterol and other lipid disorders including those which are severe, complex, and/or refractory to current treatments.